The objective of this proposal is to search for the biochemical lesion(s) responsible for Duchenne muscular dystrophy (DMD) using mononuclear leukocytes as a cell model for this genetic disease. Our hypothesis is that the high levels of creatine and creatine kinase (CK) found in serum from these patients with DMD suggests a primary disorder in creatine metabolism or CK expression. The failure to reproduce these clinical findings in dystrophic muscle cultures and the similarities between leukocytes and muscle cells with respect to creatine metabolism renders the blood monocytes from DMD patients a potential cell culture model. To examine this hypothesis, we will use peripheral blood leukocytes from dystrophic patients, their siblings, and parents, and from normal subjects to investigate abnormalities in creatine metabolism and CK expression. Our specific objectives are to identify biochemical or morphological differences between dystrophic and normal monocytes with respect to the following cellular properties and functions: 1) creatine uptake and creatine trapping, 2) creatine phosphate turnover and utilization during cellular activity, 3) CK activity and isoenzyme patterns and 4) the release of cellular CK into the medium. Furthermore, recent studies suggest that non-myogenic cells from DMD patients express a disorder in certain membrane functions and a reduction in intracellular microtubules. Therefore, we will use the dystrophic monocyte to investigate specific membrane functions such as phagocytosis and pinocytosis and their relationship to microtubule, actin or 10 nm filament organization, to determine if any abnormality exists. The mononuclear phagocyte is a powerful cellular activities and therefore is a superb cell model to gain further insights into the biochemical lesion responsible for this hereditary disease.